Corneal Neovascularization
The cornea is a transparent avascular tissue of the eye, whose transparency is essential for clarity of vision. Corneal neovascularization (CNV) is a pathology characterized by the excessive growth of blood vessels from the limbus into adjacent corneal tissues in which the new blood vessels can extend into superficial and deep corneal stroma. As well as having adverse impact on the transparency of the tissue due to the existence of the blood vessels themselves, the infiltrative growth of new blood vessels can disrupt or destroy ocular tissue resulting in widespread adverse effects.
Thus, CNV is characterized by angiogenesis which, by definition, is the formation of new blood vessels. However, CNV can be viewed as being a pathology of complex origin.
CNV is commonly associated with extended wearing of hydrogel contact lenses, presumably as a consequence of oxygen deprivation to the eye.
CNV can develop following trachoma (Chlamydia trachomatis infection), infectious keratitis including herpes simplex keratitis, viral interstitial keratitis, infections caused by staphylococcus, streptococcus, Pseudomonas or microbial keratoconjunctivitis. CNV as a consequence of ocular Pseudomonas aeruginosa infection is discussed in Xue et al (2002) Immunology and Cell Biology 80, 323-327.
CNV is also a sequela of several inflammatory diseases of the anterior segment, such as those resulting from chemical or physical insult of the eye, degenerative and traumatic disorders, dry eye with or without filamentary keratitis, progressive corneal vascularization caused by graft-versus-host disease, limbal stem cell deficiency (including idiopathic, traumatic, aniridia, autoimmune polyendocrinopathy), Stevens-Johnson syndrome, ocular pemphigoid and recurrent pterygium following surgery.
CNV has been associated with allergic conjunctivitis.
It follows from the above discussion that a suitable therapeutic approach to prevention or treatment of CNV will require addressing not only the role of angiogenesis in the condition but also the role of these other factors too, especially inflammation.
The sequelae of CNV are numerous. Thus, CNV can lead to corneal scarring, edema (swelling), lipid deposits, and inflammation that may result in vision loss. In addition, it can lead to loss of immune privilege of the eye which can affect the outcome of corneal transplantation, and worsens the prognosis of penetrating keratoplasty. In turn, corneal transplant is a treatment that many patients with severe corneal disease may ultimately need.
Current Therapies for CNV
To date, several surgical methods have been adopted for controlling CNV. Surgical methods include diathermy, for example fine needle diathermy i.e. the destruction of newly formed bold vessels in the cornea (Thatte S Nepal J Ophthalmol. 2011; 3(5):23-6) and laser photocoagulation, which seems to be effective in a subset of CNV. In the latter case a high recurrence rate has been observed. Complications also include increased inflammation which is obviously undesirable.
Photodynamic therapy has been proposed; this involves the administration of a photosensitizing compound, selectively absorbed by neovascular tissue. Activation of this compound with low energy laser light generates cytotoxic mediators, which cause selective thrombosis and destruction of newly formed vessels.
Corticosteroids have been a standard treatment for CNV. with variable and limited success. Ocular side effects commonly observed include cataract induction, glaucoma, and increased risk of infection (Jones R, 3rd, et al, Curr Opin Ophthalmol 2006; 17:163-7; McGhee C N, et al, Drug Saf 2002; 25:33-55, James E R. J Ocul Pharmacol Ther 2007; 23:403-20.)
New generation corticosteroids with broad angiostatic activities have been developed and constitute a potential therapy for CNV. One example, anecortave acetate, has been shown to be effective in animal models of CNV, as reported by Shakiba et al (2009) Recent Patents on Inflammation and Allergy Drug Discovery 3, 221-231
The anti-VEGF monoclonal antibody bevacizumab has been tested in humans showing some effect following topical administration in inhibiting CNV (Kim S W, et al. Ophthalmology 2008; 115:e33-8, Dastjerdi et al (2009) Arch Ophthalmol 127(4) 381-389.)
The anti-VEGF monoclonal antibody bevacizumab has been tested in humans showing some effect following topical administration in inhibiting CNV (Dastjerdi et al (2009) Arch Ophthalmol 127(4) 381-389). More generally the role of anti-VEGF agents as potential treatments for CNV is discussed in Shakiba et al (2009) supra).
Cyclosporin A, an immunosuppressive drug, is widely used to prevent rejection in corneal transplants. There have been reports of its effective topical use in treatment of CNV following penetrating keratoplasty to treat a fungal corneal ulcer (Sonmez B et al (2009) Int Ophthalmol. 29(2), 123-5). Topical cyclosporin A has been shown to inhibit CNV following xenografts or chemical cautery in rats (Benelli et al (1997) Invest Ophthalmol Vis Sci 38(2) 274-282). Confusingly there are also reports of cyclosporine A stimulating neovascularization in resolving sterile rheumatoid central corneal ulcers (Gottsch and Akpek (2000) Trans Am Ophthalmol Soc. 98, 81-90). Another immunosuppressive drug, rapamycin, has been shown to be effective in inhibition of CNV in a murine corneal alkaline burn model of the disease (Kwon Y S et al (2005) Invest Ophthalmol Vis Sci. 46(2), 454-60).
In unconnected disclosures, cyclosporin A, is reported to be an NK-1 receptor antagonist (Gitter et al (1995)289(3), 439-46) and it is reported that cyclosporin A has selectivity for both NK-1 and NK-2 (Munoz et al (2010) Peptides 31, 1643-8).
Bearing in mind the complex pharmacology exhibited by cyclosporin A, it has never been suggested that the potential efficacy of cyclosporin A in treating CNV is in any way connected with its NK-1 antagonist activity.
Substance P
Substance P is a C-amidated decapeptide that belongs, along with neurokinin-A, neurokinin-B, and neuropeptide-K, to the tachykinin family. The tachykinin receptor system belongs to the GPCR superfamily and comprises three subtypes of receptors, namely NK1, NK2, NK3. The principal receptor for substance P is NK-1.
Substance P is abundantly expressed in central, peripheral, and enteric nervous systems. It is also present in the peripheral sensory nerves of the cornea (Muller and Tervo (2003) Exp Eye Res, 76, 521-542).
Corneal vascularization has traditionally been studied in animal models in the field of neovascular research to test angiogenic and anti-angiogenic substances. The visibility, accessibility and avascularity of the cornea are highly advantageous and facilitate the biomicroscopic grading of the neovascular response upon topical application of test substances (Kenyon B M et al, Invest. Ophthalmol. Vis. Sci. 1996, 37; (8) 1625-1632).
In this context, Ziche et al (Ziche and Maggi (1990) Microvascular Research 40, 264-278) investigated the role of Substance P on the growth of capillary vessels in vivo and on the proliferation of cultured endothelial cells. They implanted slow release pellets containing substance P into the avascular cornea of rabbits and monitored vessel growth observing that Substance P induced a marked neovascularization and a selective NK-1 agonist also induced neovascularisation. The authors also showed that Substance P increased proliferation of endothelial cells in vitro. Moreover, a selective NK-1 agonist increased proliferation of endothelial cells in vitro whereas a selective NK-2 agonist and a selective NK-3 agonist had no significant effect.
While Ziche et al assert a direct role of Substance P in the process of neovascularization as a proangiogenic factor, their perspective was to look at neovascularization of the cornea as a convenient model of angiogenesis and they were not concerned with a physiological role of Substance P in the cornea. For example, on page 276 they state that “Further studies are needed to assess whether under in vivo conditions SP [Substance P] or other tachykinins acting on NK1 receptors can gain access to endothelial cells in concentrations relevant to exert a proliferative effect on them in such a way as to stimulate new vessel formation”. Furthermore, their experimental settings were such as to avoid the presence of inflammatory stimuli which are a well known underlying cause of the pathology of CNV in humans (see for instance page 268: “The present experiments were performed with doses of peptides which did not produce overt signs of inflammation”). Hence at no point is it suggested by Ziche et al that antagonizing the action of Substance P might be of therapeutic use in the prevention or treatment of CNV.
NK-1 Antagonists
Over 300 patents have been filed in the past two decades in the NK1 antagonist field (Huan et al (2010) Expert Opinion therapeutic patents 20(8): 1019-1045), with compounds under investigation and development for various diseases, from depression to cancer.
The only compound approved thus far for use in therapy is aprepitant and its water soluble injectable form, fosaprepitant dimeglumine, a phosphorylated prodrug which is rapidly converted to aprepitant in vivo following intravenous administration for the prevention of acute and delayed nausea and vomiting associated with cancer chemotherapy